Process for producing 17-bromo steroids



Patented July 27, 1954 PROCESS FOR PRODUCING 1'7-BROM0 STEROIDS Richard U. Schock, Waukegan, and William J. Karpel, Chicago, 111.; said Schock assignor to Abbott Laboratories, North Chicago, 111., a corporation of Illinois, and said Karpel assignor to The Gliddcn Company, Cleveland, Ohio, a corporation of Ohio No Drawing. Application September 26, 1951, Serial No. 248,448

7 Claims. 1

Our invention is concerned generally with a novel process for preparing steroid compounds. More particularly, it relates to a process for the preparation of l7-bromo-pregnanolones and pregnenolones from the corresponding pregnanclones and pregnenolones.

The l'l-bromo-pregnanolones and. pregnenolones prepared by this process are usefu1 in preparing 17-(a)-hydroxy compounds which have lones and pregnenolones are selectively bromina-ted in the l7-position by the use .of N-bromosuccinimide. We have discovered to our surprise that this brominating agent produces solely the 17-bromo-pregnanolones and pregnenolones in excellent overall yields. Even when an excess of N-bromosuccinimide is used, the pregnanolones and pregnenolones are brominated. selectively in the l'7-position and in no other position. We have the configuration present in many of the natu- 10 discovered that with this process it is possible to rally occurring adrenal hormones. The 17-hyroutinely produce 70 to 75% yields of a l'l-bromodroxy compounds are prepared from the 17- pregnanolone and pregnenolone even in the large bromo compounds by dehydrobromination, which scale quantities required in commercial producconvcrts the compound to the A unsaturated tion. These yields are significantly greater than compounds, after which this compound is in turn those obtained when using bromine as the bromiconverted to the 16,17-epoxy compound and nating agent, followed by .dehydrobromination thense to the l7-hydroxy compound. The 17- when using either a. sodium iodide-sodium bisulhydroxy compound and its 21-acyl derivatives fite reaction or when using collidine as the dehyare of current interest in synthesis .in the cortidrobromination agent. sone field, and particularly, Kendall's compound 20 We have discovered that our p o Procedes E (pregnene-4-di01-17 (a), 21-trione-3,11,20). satisfactorily without protecting the 3-hydroxy These compounds are important as adrenal up f undin pregIlaIlOlOIleS and pregnenolones hormones or in therapy requiring this type of although We prefer to protect this grouping by compound. These compounds are further useful acy a n W th an cyl substituent- W prefer to in the synthesis of similar compounds. 25 use theacetyl group as the protecting substituent. The bromination in the l'l-position of preg- Our process will operate without thebenefit of a nanolones and pregnenolones has recently been oatalystbut we prefer to use a catalyst. We have developed using bromine as the brominating used with success both of the usual brominatin agent. In this respect, reference is made to the catalysts; a light source and peroxides. The catpublication of Julian and Karpel, Journal of the alysts are usually defined as free-radical gener- American Chemical Society, vol. 72, pages 362-6, ating catalysts. We prefer as a light source the (-1950). The authors disclose the bromi-nation of usual D fl d amps used in ph t p pregnanolones and pregnenolones using a soluwork having a high wattage such as the phototion of bromine in acetic acid during which the flood lamp G. E. RFL 2 lamps currently marketed 1.7- position is brominated but during which the by the General l c c-C p ny. Similar excelzl-position and any unsaturated linkages are also lent results have been obtained by using commerbrominated. A reduction in "the amount of brocial infrared and ultraviolet lamps. We have obmine used apparently does not aid in selectively a n d x llen c s using peroxides such as brominating the l7-position. In order to prepare the orga c pcroXidc, yl Peroxidethe 17-.bromo-derivative, it then becomes neces- When brominating unsaturated pregnanolones, sary to debrominate the 21-position and any preit is desirable first to block the unsaturated carviously unsaturated linkage. The authors dehon atoms, for example, with stoichiometric brominate by oxidizing with sodium iodide or anqua t f ree m n r with chl r n us other reagent followed by reduction of the resultdichloroiodobenzene, (Berg et 211-, J ur al f ing 21-iodo derivative. This process results in Biological Chemistry, volume 162, p ge 683), b substantial loss in yield and additional expenses fore bromin i e With o uc in laborand material costs to .produce'a derivative After the reaction has taken place, the re ul n which is brominated solely in the 17-position. dihalo compound is treated with alkali-metal When conducted on a commercial scale, the cost iodide and alkali-metal bisulfite as is disclosed in of the 17-bromo derivative is multiplied several the Julian et al., Journal Of h A r n em times over the process of our invention. The cal Society publi a i n, Supradifliculties ,in debromination are thoroughly dis- By using our process, it is possible to brominate cussed by the authors in their J. A. C. S. pubpregnanolones and pregnenolones exclusively in lication. the 17-position even when an excess of N -bromo- According to the present invention, pregnanosuccinimide is used. The yields are much higher 3 than those obtained using other bromination techniques when the 17-bromo compound is desired. Using our process, it is not necessary to resort to the costly dehydrobromination techniques required by the prior art. To the best of our knowledge, this is the only process which brominates directly exclusively in the 17-position of a pregnanolone and pregnenolone. The following equation illustrates the reaction of our process:

21 OH: CH:

I Br 1%? succinimid The startin materials utilized in practicing the present invention may be represented by the following general formula:

wherein R1 is selected from the class which consists of hydroxy radicals, acyloxy radicals and hydrogen and R2 in all three formulae is a radical selected from the class which consists of keto radicals and hydrogen, and such compounds having any unsaturation in any of the rings.

The preferred starting materials are the pregnanolones and pregnenolones, which may contain free or esterified hydroxyl groupings in the molecule, and which may also contain keto groupings. We particularly prefer to use pregnanolones and pregnenolones having an acylated hydroxyl group in the 3-position and a keto group in the ll-position.

When referring to the term pregnanolones and pregnenolones we refer to compounds having the following basic structure:

and compounds having unsaturation in one or more of the rings and to compounds having an acylated hydroxy group in the 3-position.

Examples of our starting materials are: 20- pregnanone 3 (or) hydroxy 11,20-diketo-pregnane, 3-acetoxy-l1,20-diketo-pregnane and 3- benzoxy-11,20-diketo-pregnane, and the like.

In order more clearly to disclose the nature of the present invention, several specific examples illustrating the preparation of typical compounds will hereinafter be described. It should be understood, however, that this is done solely by Way of example and is intended neither to delineate the scope of the invention nor limit the ambit of the appended claims.

EXAMPLE I 1 7-br01no-1 1 -ketopregnanolone acetate To a hot solution of 36.5 g. of ll-ketopregnanolone acetate (0.095 mole) in 365 cc. of carbon tetrachloride is added 30.0 g. of N-bromosuccinimide (0.169 mole). The suspension is stirred and heated to boiling, whereupon the heating source is replaced by a photographic photofiood lamp (such as is sold by the General Electric Company under the designation G. E. RFL 2) and the contents illuminated for 5 minutes. The mixture is chilled, the solids separated by filtration and the filtrate washed with a 10% solution of sodium bisulfite to remove free bromine. After washing twice with water, the wet carbon tetrachloride is distilled in vacuo over a water bath. The crude crystalline cake is slurried with cc. of isopropyl ether and filtered. The yield of l'l-bromo-ll-ketopregnanolone acetate is 33.0 g., having a melting point of 1668 C. Upon recrystallization from isopropyl ether the compound melts at 171-2" C. Similar results are obtained with an infrared or ultraviolet source of light or by using a 10 mole percent concentration of benzoyl peroxide.

By refluxing the above crude compound with collidine, a 70-75% yield based on ll-keto pregnanolone acetate of ll-keto-A -pregnenolone acetate may be obtained. This material may then be converted to the epoxy compound and converted to the corresponding l'7-hydroxy compound, ll-keto-lfla) -hydroxy pregnanolone.

EXAMPLE II 1 7 -bromo-1 1 -ketopregnanolone acetate A mixture of 1.9 grams of ll-ketopregnanolone acetate, 20 cc. of carbon tetrachloride, 1.0 grams of N-bromosuccinimide and a few crystals of benzoyl peroxide is heated to boiling under a reflux condenser. After a short time there results a light yellow, cloudy mixture which contains insoluble succinimide. The mixture is cooled to below the boiling temperature. The mass is filtered, and the clarified filtrate is evaporated to a semicrystalline residue. The compound formed is the same compound as prepared by Example I. By refluxing the crude 17-bromo-11-ketopregnanolone acetate, formed above, with collidine, ll-keto-A -pregnenolone acetate (M. P. 164 C., no depression of melting point when admixed with an authentic sample of ll-keto- A -pregnenolone acetate) is produced.

. EXAMPLE III I 1 7 -bromo-3,9-epoxypregnane-1 1,20-dione 3.9-epoxypregnane-11,20-dione, M. P. 124 l25.5 C., was prepared by chromic acid oxidation of 3,9-epoxy-l1-keto-24,24-diphenyl-A -choladiene, M. P. 236238 C. (according to the proc ess described in Meystre et al., Helv. Chim. Acta., 30, 1037 (1947) The reaction was carried out in an analogous manner to the first example using EXAMPLE IV 17-bromo-A -pregnene-3(B) -oZ-20-one acetate Since the starting material has unsaturation in the 5,6-position, it is desirable to block the position by the addition of elemental bromine to be removed later by an alkali-metal iodide. The bromine substituted in the 17-position is accomplished by the use of the N -bromosuccinimide.

To a solution of 1.07 g. of A -pregnenolone acetate in 20 ml. of chloroform at 70 C. there is slowly added m1. of 0.3 M bromine in carbon tetrachloride solution. After warming to room temperature, the solvents are removed in vacuo. The crystalline residue is dissolved in 30 m1. of carbon tetrachloride. Then about 0.94 g. of N- bromosuccinimide is added and after heating to the boiling point, the flask is illuminated for several minutes with a 250 watt infrared lamp. The mixture is cooled and the solids removed by filtration. The solvent is then distilled from the filtrate at reduced pressure. The residual solid, 5,6,17-tribromo pregnane-lflfi) -ol-20-one acetate, M. P. 162163 (d), is dissolved in 10 m1. of benzene and to this is added a solution of 2.5 g. of sodium iodide in 10 ml. of 12A absolute alcohol. After 24 hours at room temperature, the solution is diluted with water and 50 ml. of ether is added. The layers are separated; the organic layer washed with 10% of sodium bisulfite solution, twice with water and then dried. Evaporation leaves 0.65 g. of product, M. P. 143-145" C. Recrystallization from methanol raises the melting point to 146-147 C.

EXAMPLE V 17-bromo-allopregnanolone acetate To 1.0 g. of allopregnanolone acetate dissolved in 15 cc. of carbon tetrachloride, 0.6 g. of N- bromosuccinimide and 50 mg. of benzoyl peroxide are added. The mixture is boiled under a reflux condenser for 7 minutes and after being cooled is filtered to remove succinimide. The clarified filtrate is evaporated in vacuo and the gummy residue is taken up in the minimum amount of methanol. The crude product crystallized from this solution melted at 118 to 123 C. (first crop material).

The crude product is recrystallized from methanol resulting in needles of a melting point of 129 to 130 C.

By refluxing the crude material with collidine, 16-dehydro-a1lopregnanolone acetate is produced which does not depress the melting point of an authentic specimen of this product.

Others may readily adapt the invention for use under various conditions of service, by employing one or more of the novel features disclosed, or equivalents thereof. As at present advised with respect to the apparent scope of our invention, we desire to claim the following subject matter.

We claim:

1. The process of producing a member selected from the class consisting of 17-bromo-pregnanolones and 17-bromopregnenolones, which comprises; selectively brominating only the 17 position of a member selected from the class consisting of keto pregnanolones and keto pregnenolones with N -bromosuccinimide.

2. The process of producing the compound with the formula:

wherein R1 is selected from the class which consists of hydroxy radicals, acyloxy radicals and hydrogen and R2 is oxygen, which comprises selectively bromine-ting only the 17 position of a compound of the formula with N-bromosuccinimide.

3. Process according to claim 2 wherein one of the rings is unsaturated, which comprises; first saturating the ring with a member selected from the class consisting of chlorine and bromine before specifically brominating the 17-position with N-bromosuccinimide.

4. The process of producing 17-bromo-11- ketopregnanolone acetate, which comprises; selectively brominating only the 17 position of ll-ketopregnanolone acetate with N-bromosuccinimide.

5. The process of producing 17-bromo-3,9- epoxypregnane-l1,20-dione, which comprises; selectively brominating only the 17 position 01 3,9-epoxypregnane-11,20-dione with N-bromosuccinimide.

6. The process of producing 17-bromo-A pregnene-3 3)-ol-20-one acetate, which comprises; treating A -pregnene-3(fi)-ol-20-one acetate with bromine in an'inert solvent, treating the reaction product with N-bromosuccinimide, evaporating the solvent, adding an alkali-metal iodide, extracting the reaction product with an organic solvent and washing with an alkali-metal bisulfite solution.

7. The process of producing ll-keto-A pregnenolone acetate which comprises, selectively brominating only the 17 position of 11- ketopregnanolone' acetate with N-bromosuccinimide, following by refluxing the 17-br0mo compound formed with co1lidine..

References Cited in the file of this patent Djerassi, Chemical Reviews 43, 282-285 (1948) 

1. THE PROCESS OF PRODUCING A MEMBER SELECTED FROM THE CLASS CONSISTING OF 17-BROMO-PREGNANOLONES AND 17-BROMOPREGNENOLONES, WHICH COMPRISES; SELECTIVELY BROMINATING ONLY THE 17 POSITION OF A MEMBER SELECTED FROM THE CLASS CONSISTING OF KETO PREGNANOLONES AND KETO PREGNENOLONES WITH N-BROMOSUCCINIMIDE. 